This new study found the same sort of heart risks accompany NSAIDs that don't specifically target cox-2, but still inhibit the enzyme to some degree.

That category of NSAIDs was associated with a 17 percent increase in postmenopausal women's risk of heart attack or stroke, compared to a 13 percent increase associated with NSAIDs that specifically target and inhibit cox-2.

"These are widely used drugs in this country and worldwide, so it has huge ramifications," said study author Dr. Anthony Bavry, an associate professor of cardiovascular medicine with the University of Florida's College of Medicine, in Gainesville. "Naproxen, which inhibits cox-2 more than cox-1, was associated with a 22 percent increased risk of death, heart attack or stroke," he said.

NSAIDs work by influencing cyclooxygenase (cox), an enzyme that helps regulate inflammation in the body. The enzyme comes in two forms, cox-1 and cox-2. Cox-1 helps protect the lining of the stomach and tends to promote blood clots, while cox-2 is found in the lining of blood vessels and works to prevent blood clots, Bavry explained.

Prior research has found that specifically inhibiting cox-2 can increase heart attack and stroke risk, so much so that two NSAIDs that targeted cox-2 -- Vioxx and Bextra -- were pulled from the market for safety reasons in the mid-2000s.

Bavry and his colleagues decided to test whether any NSAID that tends to inhibit cox-2 would create the same health risk, even if the drug doesn't specifically target cox-2.

The finding already has sparked some controversy, with current American Heart Association President Dr. Elliott Antman calling the findings against naproxen an "overreach."

"The totality of the evidence still leaves us comfortable recommending naproxen as a medication that can be used for a short period at a lower dose for people with risk of heart disease," Antman said.

The study is published in the July issue of Circulation: Cardiovascular Quality and Outcomes, an American Heart Association journal.

In the study, NSAIDs were sorted into three categories: those that selectively inhibit cox-2, those that appear to inhibit cox-2 more than cox-1, and those that appear to inhibit cox-1 more than cox-2.

The researchers then reviewed medical data for more than 160,000 postmenopausal women enrolled in the Women's Health Initiative, a set of clinical trials launched in 1991 to test the effects of hormone therapy. The trials required women to report use of prescription and nonprescription medications.

Within this group of women, naproxen was the most widely used NSAID that inhibited cox-2 more than cox-1, while ibuprofen (Advil, Motrin) was the most widely used NSAID that inhibited cox-1 more than cox-2.

"Although there are other agents that are in this analysis, our findings are largely applied to naproxen and ibuprofen since they were such a wide part of our study sample," Bavry said.

The doctors found a moderately increased risk of heart attack and stroke associated with use of both selective cox-2 inhibitors and those NSAIDs that affect cox-2 more than cox-1. Use of NSAIDS that inhibit cox-1, including ibuprofen, appeared to have no effect at all on heart attack or stroke risk.

Women should discuss this research with their doctor to decide whether naproxen is right for them, Bavry said.

"Many people think that naproxen is the safer NSAID," he said. "This study is counter to our previous understanding of these agents, and signals to me that we need to further research these agents for safely treating chronic pain syndromes in women."

Antman agreed that everyone should talk with their doctor if they regularly use NSAIDs.

"Please inform your physician about all medications you take, even over-the-counter medications, and do not routinely use NSAIDs for an extended period of time," he said.

But people should be careful drawing conclusions from this latest finding, Antman added. The study was not a randomized trial, he noted, and the available data left some important questions unanswered.

"We don't know if a person filled a prescription, did they actually take it and what dose did they take," he said. "There's a lot of important information that's simply not available, despite the rigor with which these authors approached their analyses," Antman explained.

"In general, the more selective against cox-2 these drugs are, the greater the risk," Antman concluded. "We should stop there, because anything else -- regardless of what you read in the paper -- becomes extremely speculative."

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